STATE-OF-THE-ART PAPER
Promoting Mechanisms of Vascular HealthCirculating Progenitor Cells, Angiogenesis, and Reverse Cholesterol Transport
Pedro R. Moreno, MD*,
Javier Sanz, MD* and
Valentin Fuster, MD, PhD*, ,*
* Zena and Michael A. Wiener Cardiovascular Institute, and the Marie-Josee and Henry R. Kravis Cardiovascular Health Center, The Mount Sinai School of Medicine, New York, New York
The Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Manuscript received November 14, 2008;
revised manuscript received January 27, 2009,
accepted February 6, 2009.
* Reprint requests and correspondence: Dr. Valentin Fuster, Mount Sinai School of Medicine, Box 1030, New York, New York 10029 (Email: valentin.fuster{at}mountsinai.org).
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Abstract
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To understand and promote vascular health, we must reduce the aggression to the vessel wall and enhance the physiologic mechanisms leading to restoration of vessel wall function. Three main defense mechanisms are responsible for maintaining cardiovascular homeostasis: the regenerative production of endothelial progenitor cells, vessel wall angiogenesis, and macrophage-mediated reverse cholesterol transport. Endothelial progenitor cells can restore vessel wall function and reduce atherosclerosis. In patients with risk factors, high levels of circulating progenitor cells increase event-free survival from cardiovascular events. Mobilization of progenitor cells includes physical and pharmacological approaches, of which exercise and statin therapy have great potential. Angiogenesis is a pivotal defense mechanism to counteract hypoxia and is needed for plaque regression. However, neovessels are susceptible for intraplaque hemorrhage, particularly in diabetes mellitus. In these patients, the haptoglobin 2-2 genotype is the more affected, and may benefit from an antioxidant approach. Finally, the reverse cholesterol transport system is the main mechanism for plaque regression. In addition to high-density lipoprotein cholesterol, apolipoprotein A-I therapies and the promotion of cholesterol efflux from macrophages by the ABCA1 and ABCG1 transporter systems hold great promise and may be available for therapeutic application in the near future.
Key Words: atherosclerosis • endothelium • angiogenesis • regression
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Abbreviations and Acronyms
| | ApoA-I = apolipoprotein A-I | | CETP = cholesterol ester transporter protein | | CVD = cardiovascular disease | | EPC = endothelial progenitor cell | | Hb = hemoglobin | | HDL = high-density lipoprotein | | HDL-C = high-density lipoprotein cholesterol | | Hp = haptoglobin |
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Independent of sex, race, or income, cardiovascular disease (CVD) is by far the leading cause of death in the world, with an unsustainable economic burden for our society (1). As a result, our health system needs to be revised to reduce cost and promote health. This implies a major shift of mentality: from disease treatment to promotion of health. At the vascular level, this can be achieved by reducing vessel wall injury and promoting physiologic repair. Vessel wall homeostasis is a fine balance between injury and the defense mechanisms of repair. This review will address these defense mechanisms to promote health, with special focus on the coronary arteries.
Atherosclerosis evolves from subendothelial retention of lipoproteins through the leaky and defective endothelium, where these plasma molecules are modified (e.g., oxidized) and become cytotoxic, proinflammatory, chemotaxic, and proatherogenic (2). The response-to-injury hypothesis considers inflammation as a central mechanism responsible for early atherogenesis (3–8). Arterial wall injury, mostly mediated by aging, diabetes, smoking, hypercholesterolemia, and hypertension, triggers an inflammatory response, a defense mechanism to restore arterial wall integrity. However, persistence of risk factor–mediated arterial wall injury leads to endothelial dysfunction, atheromatous plaque formation (9), plaque rupture, and thrombotic complications, the overall process of atherothrombosis (10,11). Simultaneously, inflammation also orchestrates a process of repair through 3 main defense mechanisms, illustrated in Figure 1. These include: 1) endothelial repair by progenitor cells; 2) plaque neovascularization; and 3) reverse cholesterol transport.
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Figure 1 Mechanisms of Vascular Health
Defense mechanisms responsible for maintaining endothelial and vessel wall homeostasis, including: 1) endothelial progenitor cells; 2) angiogenesis and plaque neovascularization; and 3) reverse cholesterol transport and plaque regression. LDL = low-density lipoprotein; MMP = matrix metalloproteinase; TF = tissue factor. Modified, with permission, from Fuster et al. (10).
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Endothelial Repair by Progenitor Cells
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Endothelial dysfunction finally leads to endothelial cell death, lipid entry, invasion of inflammatory cells, and vascular smooth muscle cell proliferation. An initial functional impairment of the endothelial monolayer with a high chance of reversibility now turns into structural damage (12). However, regeneration can occur. In 1997, Asahara et al. (13) identified bone marrow–derived circulating endothelial progenitor cells (EPCs) from the bloodstream and established their regenerative potential. EPCs are a subgroup of peripheral blood monocytes that express stem cell–like antigenic determinants including CD34 and the vascular endothelial growth factor 2 receptor (14). Other progenitor markers, including CD31+, CD133+, CD117+, P1H12+, cKit+, Sca1+, and CXCR4+, may also be relevant (14). The homing process, mediated by the activation of chemokines and perhaps activated platelets, provides the signals for dynamic trafficking of EPCs (14,15). Several studies have investigated the mechanistic protective role of EPCs in experimental animal models (16), with recent inhibition of plaque formation by local administration of EPCs in a rabbit model (17). We will now review the role of EPCs in predicting CVD in patients with risk factors.
EPC consumption, cardiovascular risk factors, and disease.
The number of circulating and colony-forming units of EPCs is associated with a lower risk score in men without history of CVD (18). A competent bone marrow can translate injury into productive EPC consumption and recruitment, restoring endothelial function. However, a high risk factor profile perpetuates injury, the bone marrow becomes incompetent, and so the EPCs number in the process of repair (19).
EPC function in subclinical CVD.
Several studies have evaluated the relationship between EPCs and the presence of subclinical atherosclerosis. In the elderly, reduced flow-mediated brachial artery reactivity correlates with dysfunctional EPCs (20). The number of circulating EPCs is 44% lower in diabetes mellitus, correlating with high levels of hemoglobin (Hb) A1c (21) and the severity of diabetic arteriopathy in different vascular territories. Thus, in diabetic patients with carotid disease, the lowest levels of EPCs are observed in patients with carotid stenosis >70% (22). EPC levels directly correlated with the ankle-brachial index, with extremely low levels observed in patients with atherosclerosis obliterans (22). Furthermore, diabetic patients with coronary artery disease show a further reduction in the number of circulating EPCs (23). Most importantly, increased concentration and function of EPCs decrease the likelihood of severe coronary disease. For every 10-colony forming unit increase in EPCs, a patient's likelihood for multivessel coronary disease declined by 20% (23).
EPCs and cardiovascular events.
The number of circulating EPCs was associated with a reduced risk for cardiac death and all other coronary events, as shown in Figure 2
(24). This and other studies suggest that decreased levels of circulating EPCs are seen in patients with coronary risk factors and reflect senescence, endothelial dysfunction, impaired vascular repair, and increased cardiovascular events.
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Figure 2 Improved Survival in Patients With High Levels of Circulating Endothelial Progenitor Cells
Cumulative event-free survival in an analysis of death from cardiovascular causes at 12 months according to levels of circulating CD34+ KDR+ endothelial progenitor cells at the time of enrollment. Reprinted, with permission, from Werner et al. (24).
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Modulating EPCs: implications for therapy.
Enhancement of EPCs is considered one of the most promising therapeutic alternatives for cardiovascular disease (25). The process of EPC mobilization leads to accelerated re-endothelialization, successfully achieved by erythropoietin and other growth factors (26,27). Physical exercise increases nitric oxide availability, improving EPC regeneration (28). Several pharmacological pathways may mobilize and increase EPCs, and statin therapy is the most studied so far (29–33). Although statins may have a direct stimulating effect on EPC synthesis and release into the circulation, the lipid-lowering and anti-inflammatory effects will reduce aggression to the vascular wall. All together will eventually mitigate inflammation and finally passivate the system (34). Other potential pharmacological approaches to enhance EPCs include the peroxisome proliferator-activated receptor agonists, and medications involved in the renin-angiotensin system (35–38). A better understanding of how EPCs generate and interact with each other (39–41), as well as the identification of specific functions through imaging technology (42,43), may significantly contribute to the enhancement of such defense mechanisms (44).
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Angiogenesis and Plaque Neovascularization
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Neovascularization is a pivotal defense mechanism to maintain homeostasis and restore healthy tissue in wound healing, myocardial necrosis, chronic ischemia, and regeneration of heart muscle by stem cell therapy (45). In the normal vessel wall, oxygen is provided to the tunica intima by direct diffusion from the lumen, whereas the tunic media and the adventitia are nurtured by vasa vasorum, maintaining metabolic homeostasis and removing waste products. When an atherosclerotic lesion evolves in the intima, the intima becomes thicker, and the distance between the deep layers of the intima and the luminal surface increases and ultimately exceeds the oxygen diffusion threshold (250 to 500 µm), resulting in local hypoxia and induction of neovascularization. Indeed, in rabbit aortic plaques thicker than 500 µm, the majority of viable macrophages present in the lipid core were severely hypoxic, glucose-depleted, and adenosine triphosphate–depleted, a condition likely leading to macrophage death and formation of a necrotic lipid core (46). As a result, plaque neovascularization, either from pre-existing endothelial cells (angiogenesis [45]) or from bone marrow–derived EPCs (vasculogenesis [47]), is an essential defense mechanism to compensate hypoxia and restore homeostasis in the vessel wall (48,49).
Major insights from the role of neovessels in atherosclerosis originally evolved from progression and regression experimental studies in primates (50). Disease progression is associated with a 10-fold increase in vessel wall flow through vasa vasorum, a defense mechanism response for the removal of waste products (51). As soon as the stimuli for progression stopped, flow through vasa vasorum started to diminish, coming back to baseline levels. Lipid content was reduced along with very low levels of inflammatory cells, leading to plaque regression (51,52). As a result, neovessels serve as a pathway for macrophages to get out of lipid-rich plaques and stabilize atherosclerotic plaques (52).
Despite all of these beneficial effects, plaque neovascularization is associated with inflammation and may paradoxically contribute to plaque rupture (53). Hence, an important question needs to be addressed. How does a defense mechanism fail and trigger complex disease? The answer appears to be intraplaque hemorrhage. Plaque neovessels are fragile structures, with single-layer endothelial cells prone to leakage and/or rupture, allowing for extravasation of red blood cells (RBCs) (48). Erythrocyte membranes are very rich in cholesterol, contributing to lipid expansion (54). In addition, RBC lysis releases free Hb, generating reactive oxygen species (ROS) and increasing lipid peroxidation and macrophage activation within the atherosclerotic plaque.
Intraplaque hemorrhage, haptoglobin, and macrophage interaction in plaque stability.
The heme iron component of Hb generates ROS and activates the proinflammatory nuclear transcription factor- B (55), leading to inflammation. The haptoglobin (Hp) pathway promotes clearance of free Hb through the Hp-Hb complex. This clearance is finally scavenged by the macrophage receptor CD163 (56). Thus, the ability of the macrophage to eliminate the Hp-Hb complex may influence plaque stability. However, the Hp genotype has been shown to play a role in disease progression (57). Two classes of alleles (Hp-1 and Hp-2) synthesize proteins that are structurally and functionally distinct. Functionally, the Hp-1 allele protein product is superior to the Hp-2 allele protein. Multiple epidemiological studies have demonstrated that diabetic individuals with the Hp 2-2 genotype (homozygous for the Hp-2 allele) are at 4 to 5 times greater risk of cardiovascular events (58–61). This is related to a reduced clearance of macrophage-Hp-Hb complex, favoring iron deposition, oxidative stress, and active macrophage accumulation (62–64). Furthermore, diabetic patients with the Hp 2-2 genotype exhibit a severe down-regulation of the macrophage scavenger receptor CD163 (65). It has been suggested that such overall accumulation of activated macrophages failing to target Hb clearance may contribute, by matrix metalloproteinase expression, to the digestion of the internal elastic lamina, and so to plaque disruption, as seen in Figure 3
(66).
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Figure 3 Hp Genotype, Inflammation, and Plaque Destabilization
The haptoglobin (Hp)-1 and -2 genotypes play opposite roles in macrophage function after plaque hemorrhage. In individuals with the Hp-1 genotype, a redox-inactive, hemoglobin (Hb)–Hp-1 complex is generated that binds to the macrophage CD163 receptor to induce the secretion of anti-inflammatory cytokines such as interleukin-10 (IL-10). Conversely, after plaque hemorrhage in individuals with the Hp-2 genotype, a redox-active Hb–Hp-2 complex is generated that produces reactive oxygen species (ROS) and induces macrophages to secrete proinflammatory cytokines by both CD163-dependent and -independent pathways, as shown. NF = nuclear transcription factor. Reprinted, with permission, from Moreno et al. (48).
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Modulating deleterious effects of Hb genotype and plaque neovascularization: implications for protective therapy.
Increased oxidative stress in diabetic individuals with the Hp 2-2 genotype may be antagonized by the use of antioxidant therapy. Although vitamin E does not prevent cardiovascular events in the overall population, a subgroup analysis of diabetic individuals with the Hp 2-2 genotype in the Heart Outcomes Prevention Evaluation study suggested a reduction in the primary composite events (67). Recent prospective studies are encouraging (68–70), but clearly require more extensive documentation before being considered for clinical application. Of interest, the Hp-Hb complex binds to apolipoprotein (Apo) A-I, inducing oxidation and leading to dysfunction of high-density lipoprotein (HDL) (71), as seen in Figure 4. Vitamin E decreased oxidative modification of HDL, improving HDL function in diabetic patients with the Hp 2-2 genotype (71).
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Figure 4 Haptoglobin Genotype and HDL Function
Hemoglobin (Hb) released intravascularly from red blood cells (RBCs) is rapidly bound by haptoglobin (Hp) protein to form an Hp-Hb complex. In Hp 2-2 diabetic individuals, the complex is cleared by the scavenger receptor CD163 more slowly than in Hp 1-1 diabetic individuals. The Hp-Hb complex can bind to apolipoprotein (Apo)A-I in high-density lipoprotein (HDL), with increased binding of Hp 2-2-Hb occurring due to its increased avidity for HDL and its increased plasma concentration. The Hp 2-2–Hb, but not the Hp 1-1–Hb complex, when bound to HDL can produce reactive oxygen species, which can oxidize protein (i.e., ApoA-I; GPx-glutatione peroxidase; lecithin cholesterol acyltransferase [LCAT]) and lipid components (cholesterol [chol]) of HDL and render the HDL dysfunctional (due to decreased reversed cholesterol transport [RCT] and antioxidant activity), proatherogenic, and prothrombotic. DM = diabetes mellitus. Reprinted, with permission, from Asleh et al. (71).
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Regarding potential therapies for modulation of plaque neovascularization, statin therapy has shown plaque regression in experimental animals (72,73) and most recently in humans by means of magnetic resonance imaging (74,75). Presumably, statins establish a concentration gradient tissue/blood of low-density lipoprotein cholesterol (LDL-C), thus favoring its removal from tissue and subsequent regression of the neovessels. However, modulating neovessel growth is subject to controversy. Proangiogenic therapy to promote the above mentioned defense mechanism might lead to neovessel growth in oncogenic regions. On the other hand, antiangiogenic therapy to prevent erythrocyte-macrophage active accumulation may have clinical detrimental effects (76–78). As a result, pharmacological or immunological modulation of angiogenesis still faces difficult obstacles before application for clinical therapy (79).
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Reverse Cholesterol Transport
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The third presumed defense mechanism to preserve vessel wall integrity is known as reverse cholesterol transport. Introduced by Glomset (80) in 1968, the term describes a process by which extrahepatic (peripheral) cholesterol returns to the liver for excretion in the bile and feces. Unesterified (free) cholesterol is toxic to cells, and on the basis of this concept, Ross and Glomset (81) proposed that atherosclerosis is the result of an imbalance between deposition and removal of arterial cholesterol after endothelial injury. This theory was further strengthened by the inverse relationship between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease. Increasing the HDL-C level by 1 mg/dl may reduce the risk of cardiovascular disease by 2% to 3%. This is consistent with the concept of a beneficial role of HDL-C, which is based on free cholesterol efflux from macrophages out of the vessel wall. This efflux occurs either by passive diffusion (82) or by interaction with the SR-BI receptor (83) or the ABCA1 transporter (84), as shown in Figure 5. Of these, the ABCA1 transporter system is the most efficient, responsible for over 50% of cholesterol efflux from macrophages to poorly lipidated ApoA-I. This pivotal protein is then converted to mature alpha-HDL after esterification. Mature HDL-C also transfers esterified cholesterol to other lipoproteins by the enzyme cholesterol ester transporter protein (CETP), increasing the efficiency of the system (85). There is also evidence that HDL-C also reduces LDL-C oxidation, and endothelial cell adhesion expression (86). In addition, HDL-C improves re-endothelialization through EPC activation and proliferation (87). Furthermore, the antiatherosclerotic role of anti-inflammatory cytokines such as interleukin-10 may be associated with HDL-C reverse cholesterol transport. As a result, increasing HDL-C may participate in several pathways to prevent CVD.
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Figure 5 Mechanisms of Reverse Cholesterol Transport
There are 3 major pathways by which HDL may mediate cholesterol efflux from cholesterol-loaded macrophages (left). The first pathway, passive diffusion, involves exchange of free cholesterol (FC) between mature spherical  -HDL and the cellular membrane. Net cholesterol efflux occurs after the conversion of FC to cholesterol ester (CE) by LCAT. In the SR-BI pathway, free cholesterol is transported to mature spherical -HDL. The third pathway involves the ABCA1 transporter. In the ABCA1 transporter pathway, the preferred acceptor of cellular cholesterol is poorly lipidated ApoA-I, which binds to the ABCA1 transporter and facilitates the efflux of cellular cholesterol from the late endocytic compartment, thereby decreasing the cholesterol content of the cell. The efflux of cholesterol and phospholipids (PL) from macrophages and other peripheral tissues results in the formation of preβ-HDL, which is ultimately converted to mature spherical -HDL after the esterification of FC to CE by LCAT. (Right) Both the SR-BI and ABCA1 transporter pathways are regulated by the oxycholesterol content of the cell. Excess cellular cholesterol is converted, at least in part, to 27-hydroxycholesterol by 27-hydroxylase. The 27-hydroxycholesterol binds to the ligand-stimulated transcription factor LXR, which, after dimerization with RXR, binds to the LXRE promoter element and increases the expression of SR-BI and the ABCA1 transporter genes. Thus, both mature and preβ-HDL facilitate the efflux of cellular cholesterol and participate in reverse cholesterol transport to the liver. Abbreviations as in Figure 4. Reprinted, with permission, from Brewer et al. (85).
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Experimental and clinical studies on HDL-C protective therapy.
The first study demonstrating atherosclerotic plaque regression with exogenous administration of HDL was performed by Badimon et al. (88) in hypercholesterolemic rabbits with significant reductions in both esterified and free cholesterol in aortic plaques. Several other studies confirmed these beneficial effects of HDL-C, mostly with the direct infusion and/or overexpression of HDL's major protein, ApoA-I (89–92). A second group of studies supporting the concept that increasing HDL-C reduces atherosclerosis relates to the CETP enzyme pathway. From an experimental point of view, the data on CETP expression have been controversial. In some studies, overexpression of CETP reduced atherosclerosis (93), whereas in others, atherosclerosis is actually increased (94,95). Studies in humans with CETP deficiency are also controversial. In some studies, CETP deficiency has been atherogenic (96,97), whereas in others, it has not (98,99). The hypothesis that HDL-C could be increased via CETP inhibition was tested in 15,000 patients randomized to torcetrapib plus atorvastatin versus atorvastatin alone. Results prove to be detrimental, with increases in death, heart failure, angina, and revascularization procedures in the combined torcetrapib plus atorvastatin group when compared to the atorvastatin group (100). The question is whether other agents with different interactions with CETP will provide favorable results. Torcetrapib was associated with activation in the renin-angiotensin-aldosterone system, perhaps in part explaining the increased risk of death in the trial. Intravascular ultrasound studies showed no changes in atheroma volume (101).
Clinical studies on niacin and on CETP deficiency or inhibition.
Niacin has been the most consistent medication to increase HDL-C, leading to significant reductions in myocardial infarction and cardiac death (102). Niacin favorably affects apolipoprotein containing lipoproteins, increasing HDL's major protein, ApoA-I (103). As monotherapy, niacin was tested in the Coronary Drug Project, which included 3,908 patients with previous myocardial infarction. This study reported a 27% decrease in nonfatal infarction and a 12% reduction in cardiac death at 15-year follow-up (104). In addition, the Stockholm Ischaemic Heart Disease Secondary Prevention Study included 900 patients with recent infarction, and combined immediate-release niacin 3.0 g/day with clofibrate 2 g/day (105). This study reported a 35% reduction in cardiac death at 4-year follow-up. The question is whether neutralization of the niacin molecule implicated in the frequent side effects of flushing can be obtained without causing other side effects. Such an agent (Cordaptive, Merck, Whitehouse Station, New Jersey) was recently reviewed by the Food and Drug Administration, which requested further studies before consideration for approval (106).
Future alternatives for reverse cholesterol transport and plaque regression.
Two potential pathways are being actively investigated for clinical implementation. These are the ABCA1 transporter and the ApoA-I system (107). Experimental overexpression of ABCA1 transporter protein is associated with a significant regression of atherosclerosis in mice (108). Both ABCA1 and ABCG1 are regulated by liver X receptor (109), and synthetic agonists of this nuclear receptor promote reverse cholesterol transport in vivo (110). Indeed, administration of such agonists has been associated with reduced atherosclerosis in mice (111).
The second potential pathway for clinical implementation is the repeated infusion/overexpression of ApoA-I, with documented regression of atherosclerosis in animal models and humans (112). Infusion of ApoA-I also shifts plaque activity to a more stable phenotype (113). One of the more interesting of these approaches is the concept of ApoA-I mimetic peptides, which mimic the antiathrosclerotic and anti-inflammatory properties of full-length ApoA-I (114). However, most peptides are not orally bioavailable and must be administered parenterally. At least 1 intravenously administered ApoA-I mimetic peptide, known as the RLT peptide (ETC-642, Esperion Therapeutics Inc., Ann Arbor, Michigan), is being studied in clinical trials. Another ApoA-I mimetic peptide is D-4F, an 18-amino acid peptide not degraded efficiently by gut peptidases and that can, therefore, be administered orally, albeit with low bioavailability (114). D-4F reduced atherosclerosis in mice (115), probably at least partly by increasing the anti-inflammatory effects of HDL-C, as well as by promoting macrophage reverse cholesterol transport (116). As a result, D-4F may improve HDL-C function, and human trials are ongoing with the aim of reducing cardiovascular risk without increasing plasma HDL-C levels.
Although infusions of HDL-C and oral ApoA-I mimetic peptides may contribute to plaque regression, this therapeutic option clearly requires more extensive documentation before being considered for clinical application.
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Conclusions
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Three main defense mechanisms are responsible for maintaining cardiovascular homeostasis: the regenerative production of EPCs, plaque neovascularization, and the reverse cholesterol transport system. EPCs can reverse endothelial dysfunction and prevent atherosclerosis in animal models. In humans with risk factors, low levels of circulating EPCs are associated with reduced event-free survival. Diabetic patients with coronary and peripheral vascular disease exhibit the lowest levels of EPCs. Mobilization of EPCs can be achieved with physical exercise and statin therapy. Regarding plaque angiogenesis, it is now established that neovessels are a pivotal defense mechanism against vessel wall hypoxia. However, they may fail and allow extravasation of erythrocytes leading to intraplaque hemorrhage. In diabetic patients, the haptoglobin 2-2 genotype is the more affected, and may benefit from an antioxidant approach. Finally, the reverse cholesterol transport system will have a very active role as a therapeutic pathway in the very near future. ApoA-1 therapies and the promotion of cholesterol efflux from macrophages by the ABCA1 and ABCG1 transporter systems hold great promise as therapeutic approaches in the fight against cardiovascular disease.
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Abstract
Endothelial Repair by Progenitor...